Metabotropic glutamate receptors (mGluRs) are a family of G protein- coupled receptors which participate in modulation of synaptic transmission, in synaptic plasticity and neurotoxicity. This proposal focused on group I mGluRs which are characterized by their coupling to phospholipase C and intracellular Ca2+ release. Despite the structural similarities, these receptors show a functional heterogeneity which can be observed in the patterns of receptor expression, their pharmacological properties, and in the activation of various intracellular signaling cascades. Recently, we have determined their differential ability to induce apoptotic cell death when expressed in heterologous systems. The main goal of this proposal is to establish definitively that the observed differential ability of the particular group I mGluRs to induce apoptosis is not restricted to a specific expression system, but is significantly present in native populations of neuronal and glial cells. It is also our goal to determine that the different toxic properties of mGluR1 and mGluR5 are not a mere reflection of their expression levels but are caused by the inherent properties of these receptors. The proposed specific aims include: (1) To create and test the necessary tools that will allow us to evaluate the relative amounts of the different group I receptors in recombinant and native systems and to experimentally modify the expression of these receptors. (2) To determine the ability of particular group I mGluRs to induce apoptosis in native populations of neuronal and glial cells. (3) To determine the ability of the particular group I receptors to induce apoptosis in cell lines with neuronal properties and in heterologous expression systems. We will use primary cultures of different populations with neuronal and glial cells in order to establish whether the expression of mGluR1 but not of mGluR5 receptors leads to apoptosis. These studies will also include experiments with primary cultures of cell obtained from genetically modified animals lacking mGluR1 or mGluR5 receptors. These studies will allow us to determine the role that mGluRs may play in triggering the mechanisms of apoptosis in populations of expressing native metabotropic glutamate receptors and to achieve a better understanding of the neurotoxic actions of glutamate which contribute to neuronal cell death.